Dr.
Eduardo Barreto. REPORT REGARDING SCIENTIFIC AND ECONOMICAL ASPECTS OF UKRAIN®
IN ORDER TO CONDUCT A PHARMACEUTICAL PRODUCT DEVELOPMENT FOR THE TREATMENT OF
VARIOUS COMMON SOLID TUMOR MALIGNANCIES AIMING FOR MARKETING AUTHORIZATION
APPLICATION (MAA) IN EUROPE
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4. Clinical experiences |
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| 2. Present options in the treatment of solid tumor malignancies |
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| 3. Characteristics of Ukrain® |
1.
General Remarks regarding the R&D-project
It may be surprising that unless the new chemical entity
called ‘Ukrainâ ’ had already passed
numerous preclinical as well as clinical studies in many countries with promissing
results since more than 15 years, this pharmaceutical compound could reach
marketing authorization application (MAA) so far only in Belarus (White Russia).
In contrary to many pharmaceutical products being registered for the treatment
of various oncological diseases during the past years and with still no clear
evidence regarding their benefit for the patients, the data refering to the
testing of Ukrainâ
seem to be much more complete.
Here it is important to define the term ‘completeness’
from different aspects. While evaluating all available data regarding Ukrainâ it becomes obvious that the producer and patent
claimer of this compound (Nowicky-Pharma, Austria) focussed his interests
much more on getting a deep scientific insight into the entire spectrum of
pharmacodynamic activities, pharmacokinetic behaviour and clinical efficacy
of his product rather than to follow a clear strategy in order to get a registration
in countries of considerable market potential as fast as possible. Even though
the entire amount of scientific data regarding Ukrainâ
let already to a precise idea about the properties of this compound and will
therefore satisfy many scientists, for formal reasons many of these data are
not supporting marketing registration related efforts.
This is not that much a result of the quality and quantity of the data but
of the methods how these data could be achieved.
At those times when scientists started to investigate the different biological aspects of Ukrainâ all the data that could be achieved being able to confirm the clinical relevance of a new chemical entity (concerning safety and eventually clinical efficacy) were usually accepted by the authorities being responsible for the registration of new pharmaceutical compounds.
Nowadays a number of guidelines and regulations define exactly
the character and mode of investigations to be performed during a registration
focussed R&D-process ("Good Manufactoring Practice", "Good
Laboratory Practice", "Good Clinical Practice").
Indisputably these guidelines and regulations improved tremendously the quality
and reliability of the entire R&D-process of new pharmaceutical products
to the benefit of the patients being treated with these compounds during the
clinical development phases and thereafter.
On the other hand it was remarkable to notice that the invention
of these new official tools considerably reduced the number of new chemical
entities reaching the MAA especially when considering smaller pharmaceutical
companies. Due to a tremendous increase of the financial budget being needed
for the conduct of the R&D-activities on the basis of those regulations
and guidelines small and medium seize pharmaceutical companies of today are
unfortunately not in the position any more to afford taking over the economical
risk to develop an inovative new chemical entity from it’s first synthesis
to marketing registration.
This is even more regretable if such companies had already invested a considerable
budget and scientific effort into the development of such a compound and if,
in addition, the refering data are expected to have a significant impact on
the improvement of the patients’ prognosis and their ‘quality
of life’. Due to a considerable amount of data regarding Ukrainâ which could be evaluated during the past years and their promissing
aspects for the treatment of patients suffering from various solid tumor malignancies
(even in disseminated stages of their disease), Ukrainâ represents an excellent example for a compound being worthwile to
legalize it’s therapeutic use by giving physicians and their patients
wide access on it - also outside of clinical trials.
According to her financial capabilities Nowicky-Pharma is therefore willing
to finance those preclinical and clinical investigations which have still
to be performed (respectively reperformed) to fulfill all the official requirements
in order to pass the registration process successfully. Nevertheless Nowicky-Pharma
is very much aware that a significant financial support is pivotal in order
to manage all the remaining strategic and operational steps.
Refering to the high quantity of promissing preclinical and clinical data which are already available, the final outcome of the clinical development program still to be performed will very probably be able to confirm the present data. Therefore, although the present data will not fully convince the authorities for the above mentioned formal reasons, they will at least minimize the risk tremendously to fail with the R&D-project. In parallel, when considering the market potential of Ukrainâ the economical effect of a marketing authorization application of this compound forces the financial risk of continuing and supporting this project into the background.
2.
Present options in the treatment of solid tumor malignancies
Before describing the specific character of Ukrainâ from different aspects it seems reasonable to focuss on the status quo of the present techniques and perspectives of pharmaceutical cancer treatment.
Due to the fact that cancer still represents the second
common cause of death in Europe and the
Nevertheless in the meantime a standart treatment could
be defined for approximately 40 % of all disseminated malignancies with the
effect of a satisfying palliative outcome usually being associated with a
prolongation of the absolute survival time. Even though in further 20 - 30
% of these patients no survival time prolongation can be achieved a significant
improvement of the patients’ ‘quality of life’ becomes evident.
Only for 20-30 % of those patients whose tumor is not curable with surgery
or radiotherapy there is no reasonable option for a successful chemotherapeutic
intervention.
It is remarkable that the improvement of the strategies focussing on supportive
treatment techniques and on the reduction of treatment related toxicities
was as important as to optimize the antitumor efficacy of new antineoplastic
compounds and treatment protocols respectively.
Therefore an optimal and individual focussed systemic antitumor therapy is always aiming the highest antitumor effect at the lowest quantity and quality of treatment related side effects.
Due to the common experience that the improvement of antitumor
efficacy is usually correlated with an increase of chemotherapeutic dosage
and therefore with an increase of undesireable side effects, a conventional
systemic chemotherapeutic regimen very often has to be combined with pharmaceutical
compounds respectively techniques (antiemetics, Folinic acid, Thio-sulfates,
colony stimulating factors, autologous bone marrow transplantation etc.) which
allows physicians to continue with a high and therefore probably effective
chemotherapeutic dose regimen without having to accept the punishing side
effects of the cytostatics.
For these reasons a modern systemic antineoplastic treatment being performed
on the basis of conventional chemotherapeutics has to focus on the entire
individual disease situation of the tumor patient rather than to follow a
strictly defined so called ‘standard regimen’.
The following table represents a list of the most important available tools of systemically applied anticancer strategies and a short and extremely simplified overview of their main direct or indirect biological activities against tumor cells (not considering specific subclasses of pharmaceutical compounds):
| Class of compound |
Biological strategy of tumor cell kill |
| Chemotherapeutics |
- Inhibition of enzymes being essential for DNA-synthesis - Induction of DNA-fragmentation - Inhibition of mRNA-synthesis - Inhibition of Tubulin-Polymerisation - Protein-Networking - Phosphorylation |
| Immunotherapeutics |
- Activation and / or increasing the quantity of immunocompetent cells of peripheral blood in order to recognize and kill tumor cells - In vivo-induction of cytokines with direct antiproliferative potential on tumor cells and / or with immunological activity by supporting cellular immune parameters to kill tumor cells - Ex vitro-in vivo Reperfusion of autologous artificially activated immunocompetent cells being primed against specific tumor cells - Monoklonal antibodies against tumor associated antigenes in order to induce tumor cell kill via antibody dependent cytotoxicity (ADCC) - Binding of tumor cell toxines to monoclonal antitumor-antibodies in order to enhance the concentration of the toxins specifically at the tumorsite |
| Hormones respectively Antihormones |
- Competitive blockage of hormone receptors on hormone receptor positive tumor cells |
It is very important to stress that most of the antineoplastic compounds just demonstrate one specific biological activity on one ore a few specific tumortypes and this is very often completely insufficient to keep tumorgrowth under control. Therefore the various treatment strategies being applied in oncology have in general to consider a combination of different compounds in order to evoke synergistic antitumor efficacy. Very often one compound with a specific antitumor activity is not only inert regarding further desired activities but counteracts even these activities.
It represents a well known phenomenon that in the course
of tumor progression the biological capacity of the immune system gradually
deteroriates (76, 109). While treating these patients with a regimen involving
chemotherapeutic agents this effect will even be amplified. Therefore many
of these patients have to receive immunostimulating compounds in addition,
predominantly not that much in order to reactivate immunological mechanisms
for a sufficient tumor cell kill but for the prevention of opportunistic infections.
In fact there is no antineoplastic compound available on market right now
offering both biological activities: a sufficient tumor cell destruction and
a significant immunostimulating property in addition.
While focussing on the class of chemotherapeutics which is widely used for
the systemic treatment of many human tumors there are a number of toxicity
problems which have to be managed by individual adaptation of the treatment
schedule and an appropriate selection of supportive steps.
These problems (like immunosuppressive activity by reduction of the total count of immunocompetent cells) is due to the fact that they generally display their cell destructive capacities not specifically on malignant cells but also on normal, non-malignant cells. It is just the higher metabolic turnover of tumor cells (compared to normal cells) which ‘sensitizes’ this celltype with the result of just a higher probability of being affected by chemotherapeutic compounds. Nevertheless, the entire spectrum of side effects being observed during chemotherapy represents the result of an unspecific character of cell killing of this compound class.
Moreover these entities do not demonstrate a prefered cumulation at the site of the tumor when applied systemically and those trials where investigators were aiming for an enhanced tumor affinity by binding chemotherapeutic molecules to anti-tumor-antibodies did not lead to an significant improvement of the clinical results.
Under these aspects Ukrainâ demonstrates a number of specific characteristics being entirely different from chemotherapeutics and immunostimulating compounds which will very likely support physicians to overcome the above mentioned clinical problems.
The new chemical entity Ukrainâ represents a semi-synthetic compound formed by purified alkaloids of the Chelidonium majus with thiophosphoric acid derivatives, triethylene-thiophosphoric acid triamide (Thio-TEPA). Three moles of Chelidonium majus alkaloids bind with one mole of Thio-TEPA. The final product contains at least 90 % Chelidonium majus alkaloid-thiophosphoric acid derivative and a maximum of 10 % of free Chelidonium majus alkaloids, while Thio-TEPA or free Aziridine ring components can not be detected.
3.1 Pharmacodynamics
The antineoplastic properties of Chelidonium majus extracts
on various histologies of skin cancer have been described in folk medicine
since many years. In order to increase the affinity of Chelidonium majus alkaloids
to the tumor tissue the herbal alkaloids were bound to Thio-TEPA (1). Due
to the high cell-cleavage turnover (proliferation rate) of tumor cells and
therefore a tremendous need of energy input, it was suggested that a phosphoric
acid containing compound being complex-bound to the Chelidonium alkaloids
might enhance the affinity of the compound to the tumor cells.
Moreover it was suggested that this new complex molecule would not only lead
to an improved therapeutic activity but also to a significant reduction of
systemic side effects being the result of the affection of non-malignant cells
apart from the tumor (1).
This suggestion could be confirmed by toxicity tests with
various animal species. In mice and rats the Ukrainâ
dosage at which 50 % of the treated animals died (LD50) was determined
at
approximately 280 mg /kg body weight (15) while the relevant therapeutic dosage
of Ukrainâ
in humans is 20 mg per application at a maximum which is lower by the factor
of 100 compared to the toxic dosage in animals.
3.1.1 Direct antineoplastic activities
Ukrainâ develops it’s antitumor activity via a dose correlated inhibition of DNA-,RNA-and protein synthesis in tumor cells (5, 9, 58, 63). Very surprisingly these inhibitory effects can not be demonstrated when conducting the test with non-malignant cells (12, 36, 63). This corresponds to the observation by laser-scanner microskopy that a much higher Ukrain-uptake can be seen in a cell nucleus of a malignant cell compared to a normal cell (36).
The National Cancer Institute in Bethesda (USA) investigated
the antineoplastic effect of Ukrainâ on 60 different human cancer
cell lines of the 8 most common types of solid human tumors (40). Surprisingly
almost all cell lines demonstrate a growth inhibition between 50 % and 100
% which, at higher concentrations, even turned into a cytolytic effect with
a reduction of cell mass. The highest sensitivity towards Ukrainâ was found in the following cell lines: Small cell lung cancer and
non small cell lung cancer, malignant melanoma, ovarian cancer, hypernephroma,
and various brain tumors.
With the chemotherapeutic compound 5-Fluorouracil (5-FU) which was investigated
under identical conditions, only in a few cell lines and under extremely high
dosages a complete growth inhibition could be achieved - while a reduction
of cell mass could never be detected (40).
In a tumor xenograft animal test a significant antitumor effect could be demonstrated with colorectal tumors, gastric tumors, large cell lung cancer, breast cancer and malignant melanoma. In nude mice experiments with human breast cancer xenografts, Ukrainâ was even able to demonstrate significant antitumor efficacy even though the breast cancer cells proved to be cis-platin resistent (64).
The cytological pattern of Ukrainâ
induced tumor cell destruction is very much following the general mechanisms
of programmed cell death by apoptosis (56, 62) being initiated by an
cell arrest in the G2M-phase of their cell cycle (116). Very interestingly
normal human cells under a Ukrainâ - concentration being 100-fold higher were not affected at all (12,
116).
In Ehrlich’s ascites tumor cells Ukrainâ irreversibly reduced the oxygen consumption
down to zero while in normal cells, after a temporarily decrease of oxygen
consumption, this parameter turned to normal within minutes (38).
Besides it’s wide spectrum of direct antiproliferative
activities on a multitude of different malignant cells Ukrainâ additionaly demonstrates
a high immunomodulatory potential - and both activities are usually never
found unified within one antitumor compound.
3.1.2 Immunostimulating activities
Ukrainâ demonstrates several immunological
activities predominantly regarding cell mediated immunity (5, 7, 8, 9, 13,
17, 18, 21, 25, 26, 44, 46, 47, 48, 49, 50, 56, 65, 66, 67, 69, 72, 76).
Thus in parallel the B-lymphocyte count, the immunglobulin level, the complement
factors and the acute phase proteins are not significantly affected, Ukrainâ obviously does not modulate
that much the humoral components of the immune system (11).
In the peripheral blood of tumor patients Ukrainâ usually enhances the number of monocytes,T-helper
cells and NK-cells and reduces the number of T-suppressor cells (9, 18, 25,
44, 46, 47, 49, 67, 72). As a result of this, the T-helper/T-suppressor ratio
is increased (48). Interestingly these parameters could not be modulated significantly
by Ukrainâ
in healthy individuals. Even after chemotherapy or radiotherapy the rosette
forming ability of the T-lymphocytes remains in a normal range (9).
Investigations regarding the in vitro mitogenic effect of Ukrainâ and Phytohaemagglutinine
(PHA) on peripheral blood cells in a cell proliferation assay demonstrated
even after a short time of preincubation of the cells with Ukrainâ that this step produced a clear synergistic effect on PHA-induced
mitogenesis resulting in significantly higher cell stimulation indices than
with PHA alone (65).
In several immunological target-effector cell systems it could be demonstrated
that Ukrainâ
significantly enhances the malignotoxic activity of macrophages, lymphocytes
and NK-cells towards different tumor cells (5, 7, 8, 17, 26, 49, 56, 66).
For these reasons Ukrainâ
has also be defined as a potent ‘biological response modifier’
(66).
When administered to tumor patients, Ukrainâ usually hardens the consistency of the tumor and demarcates it from the surrounding tissue (69). This observation is even more pronounced by a special characteristic of this compound: This characteristic is a yellow-orange autofluorescence under UV-light which allows the physician to monitor the accumulation of Ukrainâ in the tumor tissue after local or intravenous injection (4). Surprisingly, the duration of this fluorescence phenomenon can last up to 19 days after one single injection and in all the animal experiments it could be demonstrated that autofluorescence is strictly associated with a clinical response thereafter (4). In all cases where this phenomenon could not be observed a concentration of Ukrainâ at the site of the tumor and a reduction of the tumor volume could not be achieved.
Under histological aspects the responding tumors are heavily infiltrated with mononuclear cells, B-lymphocytes and cytotoxic T-cells. Numerous tumor cells are found being entirely necrotic - degenerated with vacuolated cytoplasm (69).
This tumor necrosis phenomenon very probably relates to
a further specific effect of Ukrainâ .
Technetium 99-labeled tumor necrosis factor (TNF) was systemically administered
to human tumor xenograft bearing BALB/c mice (104). Interferon or Pokeweed-Mitogen
or Ukrainâ was applied in addition in
order to investigate the potential of these compounds to enrich the immunological
extremely active cytokine TNF in the tumor tissue. The most pronounced TNF
concentration insight the tumor could be achieved with Ukrainâ .
When comparing Ukrainâ and the chemotherapeutic compound 5-FU in tumor patients regarding
the above mentioned immune parameters only with Ukrainâ
a significant upregulation could be detected which seems to be tremendously important under clinical aspects (67).
3.1.3 Activities on tumorangiogenesis
Beside it’s various direct (antiproliferative) and indirect (immunological) effects on malignant cells some new very intersesting results came up very recently assuming that Ukrainâ offers a further mode of biological action not being directed towards the tumor itself but towards the formation of tumor nutrifying blood vessels.
As any growing tissue also progressing tumors are depending
on a decreasing formation of blood vessels. This blood vessel formation (angiogenesis)
represents the result of a multistep process which is generally modulated
by a variety of different physiological apparent cytokines with pro-and antiangiogenetic
properties (bFGF, VEGF, VPF, TNF, IFN-a
/b etc.). These cytokines are produced by the tumorcells and the surrounding
tissue as well (112).
Recently in an in vitro model it could be demonstrated that even very low
concentrations of Ukrainâ could effectively inhibit the formation of capillary structures (114).
If this effect has to be interpreted as a direct Ukrain activity on the capillary
forming capacity of the endothelial cells or is mediated indirectly via a
Ukrainâ induced
release or concentration of anti-angiogenetic cytokines has still to be determined.
Thus it is known since years that the main biological function of the cytokine
TNF is characterized by the induction of a tumor necrosis via the destruction
of tumor nutrifying blood vessels and inhibition of the formation of new blood
vessels it seems to be very probable that the observations in this experiment
represent a result of the the TNF-concentrating properties of Ukrainâ (see also chapter 3.1.2).
Whatever the nature of this Ukrainâ activity might be, these data could explain why Ukrainâ is effective in the treatment of very different malignant tumors (chemotherapeutics are only effective within a very small and characteristic spectrum of tumors). If the clinical antitumoral effects of Ukrainâ are mainly a result of the biological capability to suppress blood vessel formation insight the tumor it is not surprising at all why so many different tumors are affected by Ukrainâ .
This also corresponds very well with the general experience
made by physicians that Ukrainâ treated tumor patients with
signs of clinical response at the site of the primary tumor usually never
develop additional metastases (113).
For this remarkable biological activity Ukrainâ seems to be not only an appropriate compound
to reduce the tumor mass of the primary tumor but also to suppress the formation
of metastases effectively - and this will definitely have it’s positive
impact on ‘survival time’ and ‘quality of life’. Thus
it is well known among oncologists that tumor surgery has a certain inductive
potential on metastases formation (115), a prophylactic pre- respectively
perioperational Ukrainâ course should be taken into
consideration in future.
4.1. Clinical efficacy
Up to now in total 701 people (662 patients and 39 healthy volunteers) have been recruited into 15 clinical studies regarding Ukrainâ ( 7, 10, 11, 13, 18, 21, 22, 24, 25, 27, 37, 44, 45, 47, 48, 49, 55, 67, 68, 69, 70, 72, 73, 74, 75, 92, 95, 99). Four of these studies were controlled while ten were not controlled and one trial has been conducted with healthy volunteers (phase I study). Even though the magnitude of these trials has not been conducted by following the ‘Good Clinical Practice (GCP)’-regulatories and are therefore only merely supporting the registration efforts of Nowicky-Pharma as pivotal studies, it is easy to accept that a new and serious start to develop Ukrainâ can be done from a very save and riskless position.
In order to get an idea about the tumor indications which
are predominantly worthwile to test in GCP-conformed studies it is not that
much helpful to present the available clinical data study by study. For this
purpose it seems to be more reasonable to focus on the clinical outcome of
the treatment of those 5 different tumor types which were the most common
among all 701 patients (colorectal carcinoma, lung cancer, breast
cancer, cervical and ovarian cancer). While just concentrating on these tumors
it is important to mention that in parallel many other very promissing data
will not be considered.
What is even more important is the fact that more or less all the tumor patients
having been recruited into the different Ukrainâ studies suffered from disseminated
stages of their diseases and had already passed several conventional treatment
options with finally no beneficial clinical outcome. The results of the Ukrain
treatment of the above mentioned tumor types are presented at the following
table:
| Clinical outcome |
||||
| Tumor entity |
No. of patients |
Tumor remission |
Median survival time |
Survival rate |
| Metastatic colorectal cancer |
210 |
40 % partial remission |
- |
after 21 month: 78,6 % in Ukrain group and 33 % in chemotherap. group |
| Treatment resistant lung cancer |
71 |
44,4 % objective tumor remission |
14 month (responders) 1,2 month (non-responders) |
- |
| Metastatic breast cancer |
184 |
40 % objective tumor remission |
- |
- |
| Progressive cervical and ovarian cancer |
54 |
33 % partial remission 66 % no further progression |
- |
- |
| 519 |
||||
4.2. Safety
Beside ‘clinical efficacy’ this number of Ukrainâ treated study patients also represent a reliable data pool concerning the ‘safety’ of this compound.
Ukrain has been applied in long term studies for up to 3
years in doses between 5 and 50 mg per application without any evidence of
toxic or cumulative effect.
Study reports registered the ages of patients being treated with Ukrain from
6 to 85 years. All age groups, from juveniles to higher age groups,
were represented. Approximately the same number of males and females were
treated. No reports exist on treatment during pregnancy. Experimental studies
on animals evaluated the teratogenic and mutagenic effects of Ukrainâ as negligible. In some cases a temporary increase of liver transaminases
could be detected. It is however to be assumed that these non-significant
changes appeared in association with decompensation of the tumor.
The observed side-effects of UKRAIN therapy were local pains
with intramuscular injection, and with rapid intravenous injection of larger
doses (over 20 mg per minute). In addition hot flushes, vertigo, unstable
circulation in cases of hypotonia, thirst and polyuria as well as occasional headaches during the first 30 minutes
after administration were observed.
Reported rare side-effects were, in two cases, short-lasting spastic, gastro-intestinal
pains and dyspepsia after administration.
In a few cases, fever of up to 38°C - possibly in connection with tumour decompensation - was registered. In rare cases the appearance of itching and skin rashes was observed, which could also represent the result of metastases and tumour decompensation. It is very important to mention that none of the side-effects required any special therapeutic measures.
According to current clinical experience at a clinical dosage range from 5 - 25 mg per application, UKRAIN demonstrates no acute toxicity. According to long-term observations, with therapy of up to 3 years and a total administration of 3500 mg, no cumulative effects or organ burden were observed. The side-effects of therapy which just appeared in individual cases, were always of low intensity and required no additional therapeutic measures. Allergic or anaphylactic reactions were not observed.
In order to get a rough idea about the market potential of Ukrainâ in terms of turnover in Europe after the marketing authorization application, it is important to define first the market by the indications to be treated.
Even though Ukrain is obviously effective in a remarkable
number of different malignant tumors, it seems to be appropriate to concentrate
just on those tumor diseases where the majority of the study patients suffered
from. For this purpose the tumor entities being listed in the table above
might represent the rational basis for this analysiy.
Now it is important to consider the prevalence-, incidence-and mortality rates
to be able to estimate the European market for a new chemical entity to be
registered in the above mentioned indications.
| Tumortype |
Incidence |
Prevalence |
Mortality |
| Colorectal cancer |
200.000 |
300.000 |
100.000 |
| Lung cancer |
200.000 |
310.000 |
90.000 |
| Breast Cancer |
130.000 |
170.000 |
53.000 |
| Cervical and ovarian cancer |
25.000 |
30.000 |
12.000 |
| S |
555.000 |
810.000 |
255.000 |
This table points out that every year approximately 555.000 new patients are diagnosed in Europe to be affected by one of the listed tumor diseases (the total number of patients being affected and still alive is 810.000) while at the same time 255.000 patients die from their disease.
Taking into consideration that during the first year of
availability a new pharmaceutical compound in oncology is mainly applied to
so called ‘end-stage patients’ with no
further therapeutic alternative any more, these patients are summarized in
the last column of the table.
If during the first 3 years of legalized marketing in Europe Ukrainâ penetrates this patient market
by 30 % 76.500 patients will get access to it in the 3. year
after the approval.
For a new compound in the therapeutic area of oncology this means a tremendously successful perspective!
As a semi-synthetic compound formed by the complex binding of Chelidonium majus alkaloids and thiophosphoric acid derivative Ukrainâ represents a new chemical entity for the treatment of a surprising variety of various solid tumor malignancies.
Ukrain â proved to be extremely effective in numerous in vitro models to kill tumor cells from different origin directly. This effect was much more pronounced than with standart chemotherapeutis as a reference.
In clear contrast to all available chemotherapeutic compounds Ukrainâ demonstrates several immunostimulating effects being of benefit to activate autologous mechanisms in order to attack the tumor.
Ukrainâ demostrates a specific activity being directed towards the formation of tumor nutrifying blood vessels, with the result of a fast tumor necrosis and the prevention of a tumorprogression by metastasis formation.
In 14 clinical studies Ukrainâ proved to be effective in terms of tumor control in approximately 40 % of patients suffering from very late stages of their disease with mainly no further therapeutic alternative. In lung cancer the clinical response is strongly correlated with a prolongation of survival time. In colorectal carcinoma the 21 month survival rate with Ukrain is 78,6 % with chemotherapeutics 33 %.
In clear contrast to all available chemotherapeutic compounds Ukrainâ has a very low toxic potential. Even in those cases when the patient does not benefit from the treatment in terms of tumor remission his wellbeing and therefore his quality of life is generally improved by Ukrainâ .
According to the prevalence and incidence of those tumor diseases where Ukrain could already demonstrate it’s clinical efficacy the potential market for this product is tremendously positive.
Due to the very exceptional potential of Ukrainâ and a very high proportion of patients with no further available treatment alternative who will undouptedly benefit from this compound, it is urgently recommended to support Nowicky-Pharma’s efforts sufficiently to develop Ukrainâ in order to receive marketing authorization application as soon as possible.
Laupheim, March 26th, 1998
------------------------------------
Harald von Eick (MSc)
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- Slesak B., Nowicky J.W., Harlozinska A. In Vitro Effects of Chelidonium Majus L. Alkaloid Thiophosphoric Acid Conjugates (Ukrain) on the Phenotype of Normal Human Lymphocytes. Drugs Exptl. Clin. Res., XVIII, 17, 1992
- Chlopkiewicz B., Marczewska J., Ejchart A., Anusewska E., Koziorowska J. Evaluation of Mutagenic; Genotoxic and Transforming Properties of Ukrain. Drugs Exptl. Clin. Res., XVIII, 31, 1992
- Kleinrok Z., Jagiello-Wojtowicz E., Nowicky J.W., Chodkowska A., Feldo M. Interaction between Ukrain and Aminophenazone in Analgesic Test in Rodents. Drugs Exptl. Clin. Res., XVIII, 97, 1992
- Musianowycz J., Judmajer F., Manfreda D., Spängler P., Albrecht H., Hoffmann J., Meijer D. Clinical Studies of Ukrain in Terminal Cancer Patients (Phase II). Drugs Exptl. Clin. Res., XVIII, 45, 1992
- Danilos J., Zbroja-Sontag W., Baran E., Kutylcio L., Kondratowicz L., Jusiak L. Preliminary studies on the effect of Ukrain (Tris {2-{[5BS-(5BA, 6B, 12BA)]-5B, 6, 7, 12N, 13, 14-hexahydro-13-methyl[1, 3] benzodioxolo[5, 6-C]-1-3-dioxolo[4, 5-i]phenanthridinium-6-ol}-ethaneaminyl} phosphinesulfide 6HCI) on the immunological response in patients with malignant tumours. Drugs Exptl. Clin. Res., XVIII, 55 1992
- Wyczolkowska J., Czuwaj M., Maslinski C. The immunomodulating preparation Ukrain does not induce anaphylactic sensitization in mice and guinea pigs. Drugs Exptl. Clin. Res., XVIII. 35, 1992
- Nowicky J.W., Manolakis G., Meijer D., Vatanasapt V., Brzosko W.J. Ukrain both as an anticancer and immunoregulatory agent. Drugs Exptl. Clin. Res., XVIII, 51, 1992
- Staniszewski A., Slesak B., Kolodziej J., Harlozinska-Smyrka A., Nowick J.W. Lymphocyte subsets in patients with lung cancer treated with thiophosphoric acid alkaloid derivatives from Chelidonium majus L. (Ukrain). Drugs Exptl. Clin. Res., XVIII, 62, 1992
- Sotomayor E., Rad K., Lopez D.M., Liepins A. Enhancement of macrophage tumouricidal activity by the alkaloid derivative Ukrain. In vitro and in vivo studies. Drugs Exptl. Clin. Res., XVIII, 5, 1992
- Pengsaa P., Wongpratoom W., Vatanasapt v., Udomthavornsuk B., Mairieng G., Tangvorapongchai V., Pesi M., Krusan S., Boonvisoot V., Nowicky J.W. The effects of thiophosphoric acid derivative (Ukrain) on cervical cancer, stage IB bulky. Drugs Exptl. Clin. Res., XVIII, 69, 1992
- Lohninger A., Hamler F. Chelidonium majus L. (Ukrain) in the treatment of cancer patients. Drugs Exptl. Clin. Res., XVIII, 73, 1992
- Kleinrok Z., Jagiello-Wojtowicz E., Nowicky J.W., Chodkowska A., Feldo M., Matuszek B. Some pharmacological properties of prolonged administration of Ukrain on rodents. Drugs Exptl. Clin. Res., XVIII, 93, 1992
- Juszkiewicz T., Minta M., Wlodarczyk B., Biernacki B. Teratological evaluation of Ukrain in hamsters and rats. Drugs Exptl. Clin. Res. XVIII,23, 1992
- Jagiello-Wojtowicz E., Kleinrok Z., Surmaczynska B., Baran E., Feldo B., Nowicky J.W. Effect of single and three months treatment with Ukrain on aminotransferases (ALT and AST) and on the serum protein level in rodents. Drugs Exptl. Clin. Res. XVIII, 85, 1992
- Jagiello-Wojtowicz E., Kleinrok Z., Nowicky J.W., Matuszek B., Baran E., Surmaczynska B. Effect of single and prolonged administration of Ukrain on prolactin concentration in rats. Drugs Exptl. Clin. Res. XVIII, 89, 1992
- Jagiello-Wojtowicz E., Kleinrok Z., Matuszek B., Surmaczynska B., Baran E., Nowicky W., Nowicky J.W. Effect of three months treatment with Ukrain on peripheral blood morphology in rodents. Drugs Exptl. Clin. Res. XVIII, 79, 1992
- Jagiello-Wojtowicz E., Kleinrok Z., Feldo M., Chodkowska A., Nowicky J.W. Effect of Ukrain on the efficacy of anti-epileptic drugs against maximal electroshock-induced seizures in mice. Drugs Exptl. Clin. Res. XVIII, 107, 1992
- Jagiello-Wojtowicz E., Kleinrok Z., Chodkowska A., Feldo M., Nowicky J.W. Modification of antinociceptive action of morphine by Ukrain in rodents. Drugs Exptl. Clin. Res. XVIII, 101, 1992
- Hohenwarter O., Stutzenberger K., Katinger H., Liepins A., Nowicky J.W. Selective inhibition of in vitro cell growth by the anti-tumour drug Ukrain. Drugs Exptl. Clin. Res. XVIII, 1, 1992
- Danysz A., Kokoschinegg M., Hamler F. Clinical studies of Ukrain in healthy volunteers (phase I). Drugs Exptl. Clin. Res. XVIII, 39, 1992
- Brüller W. Studies concerning the effect of Ukrain in vivo and in vitro. Drugs Exptl. Clin. Res. XVIII, 13, 1992
- Nowicky J.W. Biological Properties of Ukrain in Experimental and Clinical Investigation. International Medical Reviews, Avalanche Ltd. St. Petersburg, Russia, 1, 1, 5, 1993
- Nowicky J.W., Nowicky W., Liepins A. Cystostatic and cytotoxic effects of Ukrain on malignant cells. VIII Mediterranean Congress of Chemotherapy, 24-29 May 1992, Athens, Greece, Journal of Chemioterapia, Supplement n. 1, Volume 5, 797 1993
- Nowicky J.W. Ukrain Antineoplastic Immunostimulant. E09/029, NSC-631570, NSC-B238865, UKSR-222, W122. Drugs of the Future, Prous Science Pubhlishers, Copyright Prous Science, 18, 11, 1015, November 1993
- Kamyshentsew M.V., Voltchek, I.V., Btailovskaya I.V., Leschev A.L., Lavinsky Y.C. and Nowicky J.W. Testing Ukrain as an Anti-Infuenza Remedy. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 645, 1993
- Liepins A., Sotomayor E.M., Lopez D.M. and J.W. Nowicky. Biological Response-Modifying Properties of the Alkaloid Derivative Ukrain (NSC 631570). Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 783, 1993
- Nowicky J.W., Manolakis G., Meijer D., Vatanasapt V., Brzosko W.J. and Lohninger A. Immunological and Tumoricidal Properties of Ukrain. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 793, 1993
- Lohninger A., Musianowicz J., Judmaier F., Manfreda D., Spängler P., Albrecht H., Hoffmann J and Mejer D. Results of Phase II Clinical Studies with Ukrain. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 794, 1993
- Voltchek I.V., Nowicky J.W., Zolotukhin N.N., Kamyshentsev M.V., Miroshnichenko A.G., Leschev A.L. and Belskikh A.N. Some Immunohematological Effects of Ukrain. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 798, 1993
- Nowicky Jaroslaw W., Markowska Janina and Brzosko Witold J. Ukrain and Natural Killer Cells. Recent Advances in Chemotherapy, American Society for Microbiology, Proceedings of the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 863, 1993
- Zemskow V.S., Yaremchuk O.Ya., Susak M.Ya., Deneka E.R., Kravchenco O.V. and Kamenets
L.Ya. Experience of the Application of Ukrain on Oncological Practice
in
- Nowicky J.W., Cisak E., Liepins A., Susak Z.M.,
Semskow W. Stimulation of phagocytic activity in vitro, in vivo and in
the clinic by Ukrain. 11th Future Trends in Chemotherapy.
Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs,
24-27 April 1994, Palexpo Geneva (
- Kurik M.V., Susak Y.M., Kravchenko O.V. Some
biophysical properties of Ukrain. 11th Future Trends in Chemotherapy.
Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs,
24-27 April 1994, Palexpo Geneva (
- Lisnyak O.I., Lozjuk R. M. Biological activity
of some thiophosphamide derivatives of alkaloids with respect to influenza
virus. 11th Future Trends in Chemotherapy. Interdisciplinary
World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994,
Palexpo Geneva (
- Lozjuk R.M., Lisnyak O.I., Lozjuk L.V. Theoretical
grounds and experimental confirmation of antiviral effect of the preparation
Ukrain. 11th Future Trends in Chemotherapy. Interdisciplinary
World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994,
Palexpo Geneva (
- Brzosko W.J., Graczyk A., Konarski J., Nowicky
J.W. Synergic influence of Ukrain and protoporphyrine amino conjugates
on human malignant cell lines. 11th Future Trends in Chemotherapy.
Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs,
24-27 April 1994, Palexpo Geneva (
- Brzosko W.J., Uglianica K., Fomin K., Nowicky J.W.
Influence of Ukrain on breast cancers. 11th Future Trends
in Chemotherapy. Interdisciplinary World Congress on Antimicrobial and Anticancer
Drugs, 24-27 April 1994, Palexpo Geneva (
- Zemskow V.S., Susak Ya.M., Zemskov S.V. Ukrain
monotherapy for treamtent of colorectal cancer. 11th Future
Trends in Chemotherapy. Interdisciplinary World Congress on Antimicrobial
and Anticancer Drugs, 24-27 April 1994, Palexpo Geneva (
- Liepins A., Nowicky J.W. Selective induction
of programmed cell death (apoptosis) in malignant cells by the alkaloid
derivative Ukrain (NSC-613570). 11th Future Trends in Chemotherapy.
Interdisciplinary World Congress on Antimicrobial and Anticancer Drugs,
24-27 April 1994, Palexpo Geneva (
- Jagiello-Wojtowicz E., Kleinrok Z., Nowicky J.,
Hodkowska A., Feldo M., Matuszek B., Jablonska M., Gorzelak M. Effect
of six month treatment with Ukrain on early osteoporosis induced by ovariectomy
in rats. 11th Future Trends in Chemotherapy. Interdisciplinary
World Congress on Antimicrobial and Anticancer Drugs, 24-27 April 1994,
Palexpo Geneva (
- Nowicky J.W., Wladyslawa Nowicky, Hiesmayr W.,
Potopalsky A. Alterations of DNA, RNA and proteinsynthesis in malignant
cells under the influence of Ukrain. XVI International Cancer Congress
1994, 30 October – 5 November 1994, New Dehli,
- Ciebiada I., Korczak E., Denys A., Nowicky J.W. Effect of Ukrain preparation on immune response in mice affected by influenza virus. Journal of Chemotherapy, Vol. 7-Suppl. n. 4(101-104) – 1995
- Voltchek I., Kamyshentsev M., Lavinsky Y., Nowicky J., Medvedev Y., Litvinchuk L. Comparative Study of the Cytostatic Effects of Oliphen and Ukrain. Journal of Chemotherapy, Vol. 8 – n. 2(144-146) – 1996
- Liepins A., Nowicky J.W. Bustamante J.O., Lam E. Induction of Bimodal Programmed Cell Death in Malignant Cells by the Derivative Ukrain (NSC-631570). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 1-8
- Nowicky J.W., Hiesmayr W., Nowicky W., Liepins A. Influence of Ukrain on DNA, RNA and Protein Synthesis in Malignant Cells. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 9-20
- Nowicky J.W., Hiesmayr W. Influence of Ukrain on Human Xenografts in vitro. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 21-26
- Jin Y.M., Nowicky J.W., Liepins A. Mitogenic Properties of Ukrain (NSC-631570) on Human Peripheral Blood Monocytes: Clinical Implications. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 27-30
- Liepins A., Nowicky J.W. Modulation of Immune Effector Cell Cytolytic Activity and Tumour Growth Inhibition in vivo by Ukrain (NSC-631570). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 31-42
- Susak Y.M., Zemskov V.S., Yaremchuk O.Y., Kravchenko O.B., Yatsyk I.M., Korsh O.B. Comparison of Chemotherapy and X-ray Therapy with Ukrain Monotherapy for Colorectal Cancer. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 43-50
- Uglyanica K.N., Fomin K.A., Nefyodov L.I., Nowicky J.W., Brzosko W.J., Jankowski A. Influence of Ukrain on Patients with Surgically Treated Breast Cancer (Introductory Remarks). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 51-54
- Uglyanica K.N., Brzosko W.J., Fomin K.A., Nowicky J.W. Influence of Ukrain on Breast Cancer. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 55-62
- Uglyanica K.N., Fomin K.A., Nefyodov L.I., Nowicky
J.W., Brzosko W.J., Jankowski A. Influence of Ukrain on Patients with
Surgically Treated Breast Cancer.
- Uglyanica K.N., Fomin K.A., Nefyodov L.I., Vilkiewich T.W., Nowicky J.W., Brzosko W.J., Jankowski A. Influence of Ukrain on Patients Surgically Treated Breast Cancer. Part II. Hormonal Profile. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 67-70
- Uglyanica K.N., Fomin K.A., Nefyodov L.I., Djurd T.I., Nowicky J.W., Brzosko W.J., Jankowski A. Influence of Ukrain on Patients Surgically Treated Breast Cancer. Part III. The Immune System. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 71-74
- Uglyanica K.N., Maciuk J.R., Fomin K.A., Nefyodov L.I., Kravchuk R.I., Vinogradova L.M., Nowicky J.W., Brzosko W.J., Jankowski A. Influence of Ukrain on Patients Surgically Treated Breast Cancer. Part IV. Electromicroscopic and Cytochemical Evaluation. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 75-82
- Nefyodov L.I., Uglyanica K.N., Smirnov V.Y., Doroshenko Y.M., Fomin K.A., Nowicky J.W., Brzosko W.J. Amino Acids and their Derivatives in Blood Plasma of Patients with Breast Cancer Treated with Ukrain. Part V. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 83-86
- Nefyodov L.I., Uglyanica K.N., Smirnov V.Y., Doroshenko Y.M., Fomin K.A., Nowicky J.W., Brzosko W.J. Amino Acids and their Derivatives in Tumour Tissue from Patients with Breast Cancer Treated with Ukrain. Part VI. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 87-90
- Nowicky J.W., Hiesmayr W., Liepins A. Influence of Ukrain on Immunological Blood Parameters in vitro and in vivo. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 91-94
- Boyko V.N., Voltchek I.V., Petrov A.S., Bubnov V.P. Action of Ukrain, a Cytostatic and Immunomodulation Drug, on Effects of Irradiation. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 95-100
- Jagiello-Wojtowicz E., Kleinrok Z., Nowicky J.W., Jablonski M., Gorzelak M., Chodkowska A., Feldo M., Matuszek B. Effect of Six-Month Treatment with Ukrain on Early Osteoporosis Induced by Ovariectomy in Rats. Part I: Preliminary Studies of Bone Parameters. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 101-104
- Jagiello-Wojtowicz E., Kleinrok Z., Nowicky J.W., Chodkowska A., Feldo M., Surmaczynska B., Gorzelak M., Jablonski M. Effect of Six-Month Treatment with Ukrain on Early Osteoporosis Induced by Ovariectomy in Rats. Part II: Preliminary Studies of Peripheral Blood Parameters. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 105-108
- Jagiello-Wojtowicz E., Kleinrok Z., Nowicky J.W., Baran E. Effect of Six-Month Treatment with Ukrain on Early Osteoporosis Induced by Ovariectomy in Rats. Part III: Preliminary Studies of Some Hormone Levels. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 109-112
- Susak Y.M., Kurik M.V., Kravchenko O.V., Zemskov S.V. Certain Biophysical Properties of Ukrain. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 113 –116
- Zhalilo L.I., Susak Y.M., Zemskov S.V., Susak I.A. Influence of Ukrain on the Redox Processes of Hepatocytes. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 117-120
- Brzosko W.J., Graczyk A., Konarski J., Nowicky J.W. Synergic Influence of Ukrain and Protoporphyrin Amino Acids Conjugates on Human Malignant Cell Lines. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 121-122
- Wyczólkowska J., Michon T., Nowicky J.W. Inhibitory Effect of Thiophosphoric Acid Alkaloid Derivatives from Chelidonium majus L. (Ukrain) on Ovalbumin Antigenicity and Antiovalbumin IgE Antibody Response in Mice. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 123-128
- Jagiello-Wojtowicz E., Kleinrok Z., Chodkowska A., Nowicky J.W., Piper H., Kubiatowski T. Antinociceptive Effect of Ten Day Administration of Ukrain in Mice and Interaction of the Treatment with Morphine. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 129-132
- Jagiello-Wojtowicz E., Kleinrok Z., Nowicky J.W., Chodkowska A., Kubiatowski T., Piper H. Interaction Between Ukrain and Morphine in Their Ten-Day Treatment in Mice in the Writhing Syndrome Test. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 133-134
- Lozjuk R.M., Lisnyak O.I., Lozjuk L.V. Theoretical Grounds and Experimental Confirmation of the Antiviral Effect of the Preparation Ukrain. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 141-146
- Ciebiada I., Korczak E., Nowicky J.W., Denys A. Estimation of Direct Influence of Ukrain Preparation on Influenza viruses and the Bacteria E. coli and S. aureus. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 147-152
- Lisnyak O.I., Lozjuk R.M. Biological Activity of Some Thiophosphamide Derivatives of Alkaloids with Respect to Influenza Virus. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 153-156
- Stabuc B., Benedicic D. Ukrain with Chemotherapy in Malignant Melanoma (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 159-162
- Hamler F., Hiesmayr W., Korsh O.B., Melnyk A. Ukrain Monotherapy in Malignant Melanoma (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 163-166
- Kotsay B., Lisnyak O., Myndiuk O., Romanyshyn J., Fabri O. Ukrain Treatment of Rhabdomyosarcoma (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 167-170
- Kadan P., Korsh O.B., Melnyk A. Ukrain Therapy of Recurrent Breast Cancer with Lung Metastases (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 171-174
- Schramm E., Nowicky J.W., Godysh Y. Biophysical Effects of Ukrain Therapy in a Patient with Breast Cancer (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 175-182
- Kroiss T., Melnyk A, Korsh O.B. Ukrain Therapy in Carcinoma of the Cervix (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 183-186
- Lohninger A., Korsh O.B., Melnyk A. Combined Therapy with Ukrain and Chemotherapy in Ovarian Cancer (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 187-190
- Sakalo V.S., Korsh O.B., Melnyk A. Ukrain Treatment in a Patient with Non-Seminomatous Germ-Cell Tumour of Testis (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 191-194
- Vyas J.J., Jain V.K. Ukrain Treatment in Carcinoma of the Oesophagus (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 195-198
- Kadan P., Korsh O.B., Hiesmayr W. Ukrain in the Treatment of Urethral Recurrent Carcinoma (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 199-202
- Steinacker J., Kroiss T., Korsh O.B., Melnyk A. Ukrain Treatment in a Frontal anaplastic Grade III Astrocytoma (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 203-206
- Steinacker J., Korsh O.B., Melnyk A. Ukrain Therapy of a Recurrent Astrocytoma of the Optic Nerve (Case Report). Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 207-210
- Voltchek I.V., Liepins A., Nowicky J.W., Brzosko W.J. Potential Therapeutic Efficacy of Ukrain (NSC-631570) in AIDS-Patients with Caposi´s Sarcoma. Drugs Exptl. Clin. Res. XXII (Suppl.), 1996, pp 211-214
- Thakur M.L., De Fulvio J., Tong J., John E., McDevitt
M.R. and
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Ukrainisches Anti Cancer Institute
March 26th 1998